Chronic viral hepatitis is a major global cause of morbidity and mortality. Over the last decade, significant progress has occurred in the development of new treatments for chronic hepatitis C and hepatitis B, although management strategy of these diseases continues to evolve. More than half of patients undergoing treatment with peginterferon and ribavirin for chronic hepatitis C can achieve a sustained virological response. However, numerous patients still fail to achieve permanent viral eradication or are not candidates for initial antiviral therapy due to medical or psychosocial comorbidities which are contraindications to peginterferon and ribavirin therapy. In contrast, treatments for chronic hepatitis B with nucleoside analogues, as examples, are better tolerated, although efficacy is generally measured by prolonged viral suppression, rather than permanent cure. For both these diseases, a better understanding of mechanisms of diminished response to therapy, development of optimized treatment regimens, and/or the identification of alternative or novel medications is of critical importance. The UNC Liver Diseases Program, under the direction of Dr. Michael Fried, is extremely active in pursuing studies that focus on treatment of chronic viral hepatitis. For the purposes of this application, we will discuss an ongoing phase I/II study, funded by NCCAM/NIDDK, that investigates silymarin (milk thistle) as an alternative treatment for patients with chronic hepatitis C who failed to respond to conventional antiviral therapy (U01-AT003560, SyNCH). Furthermore, we will review a new study for chronic hepatitis B, the Hepatitis B Clinical Research Network, funded by NIDDK (U01 DK082867). Finally, we will present a detailed synopsis of an investigator initiated study that examines interferon signaling pathways in peripheral blood mononuclear cells utilizing novel methodologies. These studies provide the backbone of the mentoring program for junior faculty and fellows who are actively involved in their design, implementation, and analysis. As demonstrated within this application, mentees have been integrated into these research activities which have provided them with numerous opportunities in a mentored environment within which to develop research skills and to assert their ownership of individual projects. PUBLIC HEALTH RELEVANCE: In this competing renewal application for the K24 Mentoring Award, I will provide detailed information regarding my background in patient-oriented research and the successful clinical research and integrated mentoring program that has been developed directly as a result of this award. I will also demonstrate my continued dedication to clinical research and to a diverse group of talented junior investigators for whom I serve as primary mentor. Finally, we will provide examples of several new research initiatives that will continue to ensure effective mentored research opportunities, as well as a plan for the development of interdisciplinary research teams capable of performing translational research studies.